Fatty Acids:
Carboxylic acids occur in many molecular forms. At first it must be recalled that if the majority of the fatty acids found in lipids are monocarboxylic acids, some of the fatty acids are dicarboxylic and constitute important metabolic products of the previous ones.
To describe precisely the structure of a fatty acid molecule, one must give the length of the carbon chain (number of carbon atoms), the number of double bonds and also the exact position of these double bonds. This will define the biological reactivity of the fatty acid molecule.
Most fatty acids are straight-chain compounds with in most cases an even number of carbon atoms. Chain-lengths range from 2 to 80 carbon atoms, but commonly from 12 up to 24. With a chain length from 2 to 4 carbon atoms they are called short-chain, from 6 to 10 they are called medium-chain and 12 up to 24 they are called long-chain fatty acids. Their physical and biological properties are related to this partition in 3 classes.
Fatty acids can be further subdivided into well-defined families according to their structure:                a) Saturated fatty acids        b) Monoenoic fatty acids        c) Polyenoic fatty acids                    methylene interrupted            polymethylene interrupted                            conjugated                isolated                                                d) Mono- and multibranched fatty acids        e) Ring containing fatty acids                    cyclopropane acids            furanoid acids            epoxy acids            lipoic acid                        f) Acetylenic fatty acids        g) Hydroxy fatty acids        h) Sulfur containing fatty acids        i) Dicarboxylic acids        j) Fatty acid amides        k) Keto fatty acids.        
The simplest fatty acids are referred to as saturated fatty acids. They have no unsaturated linkages and cannot be altered by hydrogenation or halogenation. When double bonds are present, fatty acids are said unsaturated, monounsaturated (MUFA) if only one double bond is present and polyunsaturated (PUFA) if they have two or more double bonds generally separated by a single methylene group (methylene-interrupted unsaturation).
To describe these unsaturated fatty acids, two ways are offered:
The Chemist's Terminology:
The carbon atoms are counted from the carboxyl group which put the emphasis on the double bond closest to this group. As an example: 18:2 Δ9,12-octadecadienoic acid or cis-9, cis-12-octadecadienoic acid, the trivial name: linoleic acid. The double bonds have usually a Z (cis) configuration but can have also a E (trans) configuration.
The Biochemist's and Physiologist's Terminology: The double bonds are counted from the methyl group determining the metabolic family, noted by n-x (n being the total number of carbon atoms, x the position of the last double bond). The other double bonds are deduced from the first one by adding 3 (this is the most frequent structure, non-conjugated fatty acids, but sometimes by adding 2, these double bonds are said conjugated).
Thus linoleic acid (cf. FIG. 1a) or cis-9, cis-12-octadecadienoic acid is also named in the shorthand nomenclature 18:2 (n-6). This compound has 18 carbon atoms, 2 double bonds and 6 carbon atoms from the last double bond to the terminal methyl group. In the old literature it was designated 18:2ω6. 18−6=12, 12−3=9 hence D9, 12.
Saturated fatty acids have commonly straight chains and even carbon number (n=4−30). They have the general formula: CH3(CH2)nCOOH. Table 1 summarizes some saturated acids and their corresponding trivial names.
TABLE 1Most common saturated fatty acidsSystematic nameTrivial nameShorthand designationButanoic acidButyric acid 4:0Hexanoic~Caproic~ 6:0Octanoic~Caprylic~ 8:0Decanoic~Capric~10:0Dodecanoic~Lauric~12:0Tetradecanoic~Myristic~14:0Hexadecanoic~Palmitic~16:0Heptadecanoic~Margaric~17:0Octadecanoic~Stearic~18:0Eicosanoic~Arachidic~20:0Docosanoic~Behenic~22:0Tetracosanoic~Lignoceric~24:0
Monoenoic fatty acids are monounsaturated normal fatty acids which are widespread in the living world where they occur mostly as their cis-isomers. They have the general structure CH3(CH2)xCH═CH(CH2)yCOOH. They can have the unique double bond in a number of different positions, but the most common are of the n-9 series, as oleic acid from olive oil (cis-9-octadecenoic acid) and from quite all seed oils. Some important monoenoic acids are listed below:
TABLE 2Monoenoic fatty acidsSystematic nameTrivial nameShorthand designationcis-9-tetradecenoic acidMyristoleic acid14:1(n-5)cis-9-hexadecenoic~Palmitoleic~16:1(n-7)cis-6-octadecenoic~Petroselinic~18:1(n-12)cis-9-octadecenoic~Oleic~18:1(n-9)cis-11-octadecenoic~Vaccenic~18:1(n-7)cis-9-eicosenoic~Gadoleic~20:1(n-11)cis-11-eicosenoic~Gondoic~20:1(n-9)cis-13-docosenoic~Erucic~22:1(n-9)cis-15-tetracosenoic~Nervonic~24:1(n-9)
Oleic acid is probably the most common fatty acid (60-70% in olive oil). Several positional isomers of oleic acid exist with the cis double bond in the (n-12) or (n-7) position but trans-isomers are known: Elaidic acid (t9-octadecenoic acid) and t-vaccenic acid (t11-octadecenoic acid) are found in the rumen and in lipids of ruminant animals.
An unusual trans fatty acid, t3-hexadecenoic acid (trans-16:1 n-13), occurs in eukaryotic photosynthetic membranes from higher plants and green algae.
Polyenoic fatty acids are also called polyunsaturated fatty acis (PUFA). These fatty acids have 2 or more cis double bonds which are most frequently separated from each other by a single methylene group (methylene-interrupted polyenes). Linoleic acid is a typical member of this group. Some other polyunsaturated fatty acids undergo a migration of one of their double bonds which are not again methylene-interrupted and are known as conjugated fatty acids. Some unusual fatty acids do have not the regular structure with a methylene group between two double bonds, but are polymethylene-interrupted polyenes. They are found in certain classes of plants, marine invertebrates and insects. Brominated long-chain fatty acids have been isolated from phospholipids of primitive marine animals such as sponges.
The most important polyenoic fatty acids can be grouped into 2 series with a common structural feature: CH3(CH2)xCH═CH— with x=4 for the (n-6) series and with x=1 for the (n-3) series. Eicosapentaenoic acid is a common polyene of the (n-3) series having the double bonds in the 5, 8, 11, 14, and 17 positions. Table 3 summarizes the most common polyenoic fatty acids.
TABLE 3The most common polyenoic fatty acids are listed below:ShorthandSystematic nameTrivial namedesignation9,12-octadecadienoic acidLinoleic acid18:2(n-6)6,9,12-octadecatrienoic~γ-Linolenic~18:3(n-6)8,11,14-eicosatrienoic~Dihomo-γ-linolenic~20:3(n-6)5,8,11,14-eicosatetraenoic~Arachidonic~20:4(n-6)7,10,13,16-docosatetraenoic~—22:4(n-6)4,7,10,13,16-docosapentaenoic~—22:5(n-6)9,12,15-octadecatrienoic~α-Linolenic~18:3(n-3)6,9,12,15-octadecatetraenoic~Stearidonic~18:4(n-3)8,11,14,17-eicosatetraenoic~—20:4(n-3)5,8,11,14,17-eicosapentaenoic~EPA20:5(n-3)7,10,13,16,19-docosapentaenoic~DPA22:5(n-3)4,7,10,13,16,19-docosahexaenoic~DHA22:6(n-3)5,8,11-eicosatrienoic~Mead acid20:3(n-9)
The most common polyene acids are octadecatrienoic acids (7 species are known). Eleostearic acid (9c11t13t) is found in tong oil and had an industrial importance, calendic acid (8t10t12c) is found in Calendula officinalis and catalpic acid (9c11t13c) is found in Catalpa ovata. 
Recently, novel polyene fatty acids with different chain lengths and varying unsaturation were described: 16:5, 18:4, 20:5, 20:6, and unexpectedly 22:7. All these species have in common 4 conjugated all-cis double bonds as in 18:4 with their position in 6, 8, 10, and 12, the novel conjugated docosaheptadecanoic acid having its double bonds in 4, 7, 9, 11, 13, 16, and 19, it was named stellaheptaenoic acid.
Among the unsaturated polymethylene-interrupted fatty acids found in the plant kingdom those with a cis-5 ethylenic bond are present in various sources. The three most frequent fatty acids with that structure are taxoleic acid (all-cis-5,9-18:2), pinolenic acid (all-cis-5,9,12-18:3) which is found in seeds of conifers, Teucrium and also in tall oil, and sciadonic acid (all-cis-5,11,14-20:3). These fatty acids are present in seed oil at levels from about 1% up to 25%. Similar species with 4 double bonds are also described.
Some isoprenoid fatty acids are known. In this group, the most interesting is retinoic acid (cf. FIG. 1a) which derives from retinol and has important functions in cell regulation.
Mono- and multibranched fatty acids, preferably monomethyl branched fatty acids are found in animal and microbial lipids, e.g. mycobacteria. As for hydrocarbons, they have generally either an iso- or an anteiso-structure. For instance, 14-methyl pentadecanoic acid (isopalmitic acid) is of the iso-series and 13-methyl pentadecanoic acid is of the corresponding anteiso-series. Further examples for branched fatty acids are pristanic acid and phytanic acid as shown in FIG. 1a. 
Some fatty acids contain either in the chain a cyclopropane ring (present in bacterial lipids) or a cyclopropene ring (present in some seed oils), or at the end of the chain a cyclopentene ring (seed oils). Among cyclopropane acids, lactobacillic acid (11,12-methyleneoctadecanoic acid) is found mainly in gram-negative bacteriae. Another cyclopropane fatty acid (9,10-methylenehexadecanoic acid) was recently shown to be present in phospholipids of heart and liver mitochondria.
Cyclopropene acids are found in Malvales seed oils, and Baobab, Kapok and Mowrah seed oils. Among cyclopentenyl acids, Chaulmoogric acid is found in chaulmoogra oil from seeds of Flacourtiaceae (Hydnocarpus), which was used in folk medicine for treatment of leprosy.
Epoxy acids are present in a number of seed oils. The natural species are all C18 compounds, saturated on unsaturated. For example, 9,10-epoxystearic and 9,10-epoxyoctadec-12-enoic (coronaric acid) acids are found in sunflower seeds (Chrysanthemum).
Lipoic acid (cf. FIG. 1b) was first considered as a microbial growth factor but it was found not only in yeast but also in beef liver from which it was first isolated in pure form. Lipoic acid was named also thioctic acid or 1,2-dithiolane-3-pentanoic acid. After its absorption, this acid is reduced enzymatically by NADH or NADPH to dihydrolipoic acid (or 6,8-dithiane octanoic acid) in various tissues.
First shown necessary for bacteria, lipoic acid was demonstrated to be a coenzyme in the glycine cleavage system and in the dehydrogenase complex. Now, lipoic acid is considered as an efficient antioxidant since with its reduced form it constitutes a redox couple via modulation of NADH/NAD ratio. Consequently, lipoic acid has gained a special interest as a therapeutic agent. It can scavenge hydroxyl and peroxyl radicals but also chelates transition metals. It is also considered that lipoic acid is perhaps the most powerful of all the antioxidants, it may offer an efficient protection against many heart diseases, it is currently used to relieve the complications of diabetes.
Acetylenic fatty acids, also known as ethynoic acids, include fatty acids which contain a triple bond and eventually one or two double bonds. For instance, tariric acid (6-octadecynoic acid) was found in tariri seeds from Picramnia sow, a plant indigenous to Guatemala. Table 4 shows further examples of acetylenic fatty acids.
TABLE 4Acetylenic fatty acidsSystematic nameTrivial name6-octadecynoic acidTariric acidt11-octadecen-9-ynoic~Santalbic or Ximenynic~9-octadecynoic~Stearolic~6-octadecen-9-ynoic~6,9-octadecenynoic~t10-heptadecen-8-ynoic~Pyrulic~9-octadecen-12-ynoic~Crepenynic~t7,t11-octadecadiene-9-ynoic~Heisteric~t8,t10-octadecadiene-12-ynoic~—5,8,11,14-eicosatetraynoic~ETYA
In hydroxy fatty acids the hydroxyl group may occur at various positions in the carbon chain which can be saturated or monoenoic. Some polyhydroxy fatty acids are known, which are most frequently produced by lipoxygenase activities. 2-Hydroxy acids (or α-hydroxy acids) are found in plants (chain from 12 up to 24 carbon atoms) and in animal wool waxes, skin lipids and specialized tissues, mainly in brain. 2-Hydroxytetracosanoic acid (cerebronic acid) and 2-hydroxy-15-tetracosenoic acid (hydroxynervonic acid) are constituents of the ceramide part of cerebrosides and 3-hydroxy acids (or β-hydroxy acids) occur in some bacterial lipids. Further examples are ricinoleic acid (12-hydroxy-9-octadecenoic acid) which characterizes castor bean oil and lesquerolic acid, the C20 homologue of ricinoleic acid (14-hydroxy-11-eicosenoic acid).
Although the dicarboxylic acids do not occur in appreciable amounts as components of animal or vegetal lipids, they are in general important metabolic products of fatty acids since they originate from them by oxidation. They have the general type formula: HOOC—(CH2)n—COOH. Short-chain dicarboxylic acids are of great importance in the general metabolism and up to n=3 they cannot be considered as lipids since their water solubility is important. The simplest of these intermediates is oxalic acid (n=0), the others are malonic (n=1), succinic (n=2) and glutaric (n=3) acids. The other lipid members of the group found in natural products or from synthesis have a “n” value from 4 up to 21. Examples thereof are: adipic acid (n=4), pimelic acid (n=5), suberic acid (n=6), azelaic acid (n=7), sebacic acid (n=8), brassylic acid (n=11), and thapsic acid (n=14).
Ribose and Deoxyribose:
Ribose and deoxyribose are pentoses. Ribose is also called ribofuranose because of the structural relationship to furane. The only structural difference between ribose and deoxyribose is the loss of an hydroxy group in position 2′C of the heterocyclic ring. FIG. 2 shows the structures of ribose and deoxyribose.
Nucleosides and Nucleotides:
These are compounds in which a purine or pyrimidine base is covalently bound to a sugar. If the base is bound to ribose the result is a ribonucleoside (base+sugar=nucleoside), and if bound to deoxyribose then the nucleoside is deoxyribonucleoside. In deoxyribose the OH-group on 2′C is replaced with hydrogen so becomes deoxy.
The bonding between the base and the sugar involves 1′C OH-group of the sugar, and the N9 nitrogen of a purine or N1 of a pyrimidine in an N-beta-glycosidic linkage. The nucleosides containing deoxyribose possess the same type of glycosidic linkage.
FIG. 2 shows the three purine bases uracil, cytosine, and thymine.
TABLE 5NomenclatureRibonucleotide-5-BaseRibonucleosidemonophosphateAdenineAdenosine (A)AMPGuanineGuanosine (G)GMPUracilUridine (U)UMPCytosineCytidine (C)CMPThymineThymidine (T)TMPDeoxyRibonucleotide-5-BaseDeoxyRibonucleosidemonophosphateAdenineDeoxyadenosine (dA)dAMPGuanineDeoxyguanosine (dG)dGMPUracilDeoxyuridine (dU)dUMPCytosineDeoxycytidine (dC)dCMPThymineDeoxythymidine (dT)dTMP
In order to distinguish the numbering of the sugar ring and numbering of the bases the sugar numbers are primed, e.g. 3′5′. Thus, 5′ refers to 5′C of the sugar ring.
These are phosphate esters of the nucleosides and they are fairly strong acids. The phosphoric acid is always esterified to the sugar group (base+sugar+phosphate=nucleotide). The phosphoric acid could be located on the 2′, 3′ or 5′C of the sugar residue. However natural ribonucleotides and deoxyribonucleotides have the phosphoric acid on the 5′C position.
The phosphoric acid can undergo further phosphorylation to produce diphosphates and triphosphates, e.g. ADP and ATP. So for each nucleotide monophosphate there is also a nucleotide diphosphate and a nucleotide triphosphate. The di and tri nucleotides do not occur in DNA or RNA only the monophosphate nucleotides. The di and triphosphate nucleotides do occur naturally, and play very important roles in many aspects of biochemical metabolism.
Object of the present invention is to provide novel compounds and novel drug combinations which can be used for prophylaxis and/or treatment of a variety of diseases and disorders comprising diabetes mellitus Type I and Type II, inflammation, cancer, necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), neuropathic diseases, neuropathic pain and polyneuropathy, peripheral and/or central nerve diseases, degradation of the peripheral and/or central nerve system, heavy metal poisoning, ishemic diseases and ishemic heart disease, liver diseases and dysfunction of liver, allergies, cardiovascular diseases, Chlamydia pneumoniae, and retroviral infections (HIV, AIDS), together with methods for said treatment and pharmaceutical compositions used within said methods.
This object is solved by the disclosure of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the examples and the figures of the present application.